Although progress towards implementation of international agreements since publication of the UCL-Lancet Commission on Migration and Health in December, 2018, has been slow, global trends in migration and forced displace...Although progress towards implementation of international agreements since publication of the UCL-Lancet Commission on Migration and Health in December, 2018, has been slow, global trends in migration and forced displacement have continued to rise. However, the COVID-19 pandemic showed that reaching refugees and migrants with health interventions is feasible with political will. The benefits of refugee-inclusive and migrant-inclusive health-care systems during emergencies (eg, COVID-19 and the war in Ukraine) are apparent, with numerous examples of inclusive policy making being rapidly introduced and innovative models developed to support health-care access, including preventive measures such as vaccination. Lessons from these successes should be learned and incorporated into future policy and practice. However, global political and financial uncertainty and disruption-combined with multiple conflicts and natural disasters-have increased individuals' need to move, which will continue to be exacerbated by the climate crisis. Although new conflicts and exacerbations of existing ones have led to a rise in forced displacement within and across national borders, labour migration has also risen dramatically, with the pandemic highlighting the health and social needs of these groups globally. The need for strong leadership and accountability, engagement of policy makers in the highest-level fora, and improved access to quality health services for refugees and migrants has never been greater. In this Review, nearly 8 years after the UCL-Lancet Commission on Migration and Health was published, we renew our call for action to: (1) improve health-care access and optimise outcomes for refugees and migrants by emphasising health in all migration and forced displacement policies; (2) establish data systems to monitor progress, together with appropriate use of new technologies to improve access, prevent harm, and safeguard privacy; (3) support research on adaptation to and mitigation of the health consequences of climate change on refugees and migrants; and (4) renew focus on the political determinants of health outcomes for people on the move. At this pivotal moment, with geopolitical, sociodemographic, and environmental turmoil, political leaders and societies can shape a better future by leveraging the human capital of migrants and upholding the human rights and dignity of all.
BACKGROUND: Human papillomavirus (HPV) vaccination is a key component of global cervical cancer elimination strategies. While substantial declines in cervical cancer incidence have been observed in several countries, evi...BACKGROUND: Human papillomavirus (HPV) vaccination is a key component of global cervical cancer elimination strategies. While substantial declines in cervical cancer incidence have been observed in several countries, evidence of its effect on mortality is scarce. England introduced a national HPV vaccination programme in 2008 for girls aged 12-13 years (achieving 80-90% coverage before the COVID-19 pandemic), with a catch-up campaign in 2008-10 for girls aged 14-18 years. We aimed to investigate trends in cervical cancer mortality and to estimate the reduction in cervical cancer deaths in young women in England following the introduction of HPV vaccination. METHODS: We analysed population-based cervical cancer mortality data from England between 2001 and 2024 among women aged 20-24, 25-29, and 30-34 years. HPV vaccination coverage by birth cohort was obtained from official reports and used to estimate, for each age group and calendar year of death, the proportion of women who had been vaccinated. We plotted observed and adjusted age-specific mortality rates against year of death and overlaid a smoothed curve. Poisson regression applied to the numbers of deaths was used to estimate the relative risk reduction in vaccinated women compared with what was expected in the absence of vaccination, assuming no herd immunity. Confidence intervals were obtained by inverting the likelihood ratio test. FINDINGS: In women aged 20-24 years between 2020 and 2024, in whom vaccination coverage was around 88-90% at age 12-13 years, no deaths occurred, compared with 23·1 expected deaths based on historical rates, corresponding to a mortality reduction of 100% (95% CI 84-100). In earlier birth cohorts, who were offered vaccination up to age 18 years with coverage of around 63-87%, mortality reductions of 80% (51-94) in women aged 20-24 years in 2015-19, and 69% (55-79) in women aged 25-29 years in 2020-24 were observed. The relative risk reduction in vaccinated women was estimated from population-level data to be 100% (95% CI 81 to 100) in women aged 20-24 years, 100% (89 to 100) in those aged 25-29 years, and 63% (-13 to 100) in those aged 30-34 years. Up until the end of 2024, HPV vaccination in England was associated with a reduction of around 199·6 cervical cancer deaths (95% CI 125·0-274·2). INTERPRETATION: Our findings provide the first robust national-level evidence, albeit observational, that high HPV vaccination coverage is associated with a substantial reduction in cervical cancer deaths. This is shown by the substantial decrease in cervical cancer deaths observed among women aged 20-29 years in England, particularly among those vaccinated at ages 12-13 years. These findings support the achievability of the WHO goal of eliminating cervical cancer as a public health problem, and efforts should be made to achieve high vaccine uptake among young adolescents globally. FUNDING: Cancer Research UK.
BACKGROUND: There is conflicting evidence regarding the merits of patellar resurfacing during total knee replacement (TKR), as previous randomised controlled trials (RCTs) have been under-powered and with follow-up of te...BACKGROUND: There is conflicting evidence regarding the merits of patellar resurfacing during total knee replacement (TKR), as previous randomised controlled trials (RCTs) have been under-powered and with follow-up of ten years or less. METHODS: A pragmatic, multicentre, open-label RCT was initiated in 1999 in the UK. Within a partial-factorial design, participants were randomly allocated to receive or not receive patellar resurfacing during primary TKR and were followed up for 20 years. Adult (aged ≥18 years) patients due to have a primary TKR under the care of a collaborating surgeon were eligible. Participants were allocated (1:1) using an automated telephone service stratified by surgeon, with minimisation according to the patients' age (<60 years, 60-79 years, ≥80 years), sex, and location of d isease. The primary outcome measure was the Oxford Knee Score (OKS), analysed using repeated measures mixed-effects linear regression analysis with marginal differences reported. Secondary measures included the 12-Item Short Form Health Survey (SF-12), the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L), costs, cost-effectiveness, and subsequent knee surgery. This trial is registered with ISRCTN Registry, ISRCTN45837371. FINDINGS: Between April 8, 1999, and Jan 13, 2003, 1715 participants (955 female and 760 male; mean age 70 years [SD 8], mean BMI 29·7 kg/m) were randomly assigned: 861 to patellar resurfacing and 854 to no resurfacing. At the 20-year follow-up, 132 participants in the patellar resurfacing group and 110 participants in the non-resurfacing group provided outcome data, although marginal differences included earlier data for participants who died or had missing 20-year data. The marginal difference in OKS over the whole 20-year follow-up was 0·76 (95% CI -0·08 to 1·59; p=0·076) in favour of patellar resurfacing. During the 20-year follow-up period, although not significant, differences in OKS, SF-12, and EQ-5D-3L, readmissions, minor or intermediate operations, patella-related operations, major operations, and complications all favoured patellar resurfacing. At 20 years, the resurfaced group accrued significantly more quality-adjusted life-years (QALYs) than the non-resurfaced group (7·295 vs 6·884; difference 0·380, 95% CI 0·061 to 0·700; p=0·020). However, QALY differences were smaller in a sensitivity analysis assuming no difference in mortality (7·209 vs 6·964; difference 0·183, 95% CI -0·034 to 0·400; p=0·10). The cost of readmissions was non-significantly lower in the resurfaced group and offset the higher cost of primary TKR; therefore, overall 20-year health-care costs per participant were similar (£10 825 vs £10 889; difference -£6, 95% CI -£721 to £708; p=0·99). INTERPRETATION: There was no significant difference in primary outcome (OKS) or other clinical endpoints. However, as clinical differences tend to support patellar resurfacing, the resurfacing group had significantly higher QALYs. There was no difference in costs over the 20-year period, and patellar resurfacing had a 99% probability of being cost-effective at any threshold above £10 000 per QALY gained. The evidence is therefore weighted towards resurfacing being the approach of first choice. FUNDING: UK National Institute for Health and Care Research Health Technology Assessment Programme.
BACKGROUND: Previously considered rare, penicillin-susceptible Staphylococcus aureus (PSSA) bacteraemia has re-emerged worldwide. Although benzylpenicillin might offer advantages in terms of pharmacokinetic and adverse e...BACKGROUND: Previously considered rare, penicillin-susceptible Staphylococcus aureus (PSSA) bacteraemia has re-emerged worldwide. Although benzylpenicillin might offer advantages in terms of pharmacokinetic and adverse effect profiles, anti-staphylococcal penicillins are recommended for serious infections because of concern over undetected penicillin resistance. We aimed to compare benzylpenicillin with anti-staphylococcal penicillins (cloxacillin or flucloxacillin) for the treatment of PSSA bacteraemia in adults. METHODS: This investigator-initiated, international, multicentre, open-label, non-inferiority, randomised controlled trial was conducted within the PSSA silo of the backbone domain of the ongoing S aureus Network Adaptive Platform (SNAP) trial. We enrolled patients of all ages who were admitted with S aureus bacteraemia at 67 hospitals across Australia, New Zealand, Canada, Israel, the Netherlands, the UK, Singapore, and South Africa. Herein, we report results for adult patients (aged ≥18 years). Participants were randomly allocated 1:1 to receive either benzylpenicillin, or flucloxacillin or cloxacillin. Trial staff, staff caring for participants, and participants were aware of the treatment allocated and received. Cloxacillin was used only where flucloxacillin was not available (ie, Canada, Israel, Singapore, and South Africa). Recommended standard dosing for benzylpenicillin was 1·8 g intravenously once every 4 h or 2·4 g once every 6 h; for flucloxacillin 2·0 g intravenously once every 6 h; and for cloxacillin 2·0 g intravenously once every 4 h. The primary outcome was all-cause mortality 90 days after platform entry, assessed in the intention-to-treat population, including all patients with available data. The primary outcome was analysed by use of a hierarchical Bayesian logistic regression model, with non-inferiority of benzylpenicillin defined as an adjusted odds ratio (OR) of less than 1·20. Analyses occurred after every 500 participants reached 90-day follow-up. The SNAP trial is registered with ClinicalTrials.gov (NCT05137119) and is ongoing. FINDINGS: Following the fourth interim analysis, the data and safety monitoring committee recommended ceasing recruitment before prespecified stopping thresholds were reached because of increased acute kidney injury (AKI) in participants receiving flucloxacillin or cloxacillin, and the PSSA silo was closed for recruitment on Aug 7, 2024. Between Feb 18, 2022, and June 21, 2024, of 493 adults with PSSA bacteraemia, 125 were randomly assigned to the flucloxacillin or cloxacillin group and 156 to the benzylpenicillin group. The median age was 67 years (IQR 56-77), 87 (31%) were female, and 194 (69%) were male. 21 (14%) of 152 in the benzylpenicillin group and 26 (22%) of 121 in the flucloxacillin or cloxacillin group met the primary outcome of death at 90 days (adjusted OR 0·67, 95% credible interval [CrI] 0·35-1·28), with a posterior probability of benzylpenicillin non-inferiority of 96·1% and of benzylpenicillin superiority of 88·9%. AKI occurred in 17 (11%) of 153 patients in the benzylpenicillin group and 27 (22%) of 124 patients in the flucloxacillin or cloxacillin group (adjusted OR 0·50, 95% CrI 0·26-0·94), corresponding to a posterior probability of non-inferiority of benzylpenicillin of 99·8% and superiority of benzylpenicillin of 98·4%. Seven total serious adverse reactions were reported from six (4%) of 156 participants in the benzylpenicillin group and ten were reported from nine (7%) of 125 participants in the flucloxacillin or cloxacillin group. INTERPRETATION: Although the prespecified non-inferiority criterion for benzylpenicillin was not met, the probability of benzylpenicillin being non-inferior for mortality, along with a reduction in risk of AKI, indicates that benzylpenicillin should be preferred over flucloxacillin or cloxacillin for treatment of PSSA bacteraemia in adults. FUNDING: National Health and Medical Research Council, Medical Research Future Fund, Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, UMC Utrecht, ZonMW Good Use of Medicines programme, Health Research Council of New Zealand, Starship Foundation, National Healthcare Group Fund, National Medical Research Council, National Institute for Health and Care Research, Medical Research Council, and Paterson Family Foundation.
The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and co...The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. We aimed to systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.
Dimopoulos MA, Schjesvold F, Fu C
… +45 more, Hartley-Brown MA, Gomez C, Reece D, Mikala G, Alkharabsheh O, Parrish C, de Queiroz Crusoé E, Gálvez K, Idrobo H, White D, Gupta R, Lee C, Liu CJ, Quach H, Wang Y, Cerchione C, Forsyth C, Hungria V, Kalaskar P, Graklanov V, Ho PJ, Klaiber-Hakimi M, Kwong YL, Louzada M, Mazumder A, Miles O, Nagarajan C, Prasad SVSS, Raab MS, Varga G, von der Heyde E, Xia Z, Ochoa PA, Oriol A, Yuda J, Kuroda J, Gong J, Zhou Z, Maciag P, Yu B, Rocci A, Koo P, Katz J, Richardson PG, SUCCESSOR-2 Trial Investigators
BACKGROUND: A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 li...BACKGROUND: A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs. The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone. METHODS: This phase 3, open-label, randomised controlled trial was conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Interactive response technology was used to randomly assign patients, stratified by age (≤70 years or >70 years), number of previous lines of therapy (≤2 or >2), and International Staging System stage (I, II, or III). Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m twice weekly or 70 mg/m weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly). In stage 1, mezigdomide dosing across three levels was optimised. In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone. The primary endpoint was progression-free survival (PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages. No imputation was planned for missing efficacy endpoint values or missing safety evaluations. The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00). The trial is active but not recruiting. FINDINGS: Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4). At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5). Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression. INTERPRETATION: Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need. FUNDING: Bristol Myers Squibb.